The invention described herein relates to methods for treating rosacea.
Rosacea is a chronic skin condition characterized by recurrent episodes of flushing, erythema, vasodilation, telangiectasia, edema, papules, pustules, hyperplasia, fibroplasia, itching, burning, pain, and skin tightness. Symptoms of rosacea are exacerbated by sun exposure, hot weather, immersion in hot water, high humidity, sweating, exercise, emotional stress, and spicy food. The skin condition usually begins between the ages of 30 to 50 and occurs more frequently in women than men.
The etiology of rosacea is not well understood, but it has been presumed to be caused by an as yet unidentified infectious agent. Unfortunately, antibiotic administration yields only marginal improvement (see, e.g., Dahl et al., Archives of Dermatology 134: 679–683, 1998; Bamford et al., Archives of Dermatology 135: 659–663, 1999). Therefore, there is a clear need for the identification of new targets in the pathology of rosacea, and the development of drugs that affect these new targets.
Bradykinins are autocoids, that is, they are hormones that are synthesized locally and act locally. This local effect is due to the short half-life (less than 30 seconds) of bradykinins and their almost complete destruction in the first pass through the pulmonary circulation (Ferreira and Vane, Chemotherap. 30: 317, 1967).
The major effects induced by bradykinins are vasodilation, increased vascular permeability, and inflammation. The inflammatory process involves the infiltration of neutrophils, macrophages, lymphocytes, mast cells, and other lamina proprira cells, including fibroblasts, to the site of inflammation. These inflammatory cells then function to synthesize and release several arachidonic acid-related mediators of inflammation, such as prostaglandins, leukotrienes, and thromboxanes. Bradykinins also lower blood pressure, participate in blood clotting and complement reactions, and cause pain.
The group of bradykinins, which includes Lys-bradykinin (kallidin) and Met-Lys bradykinin, as well as bradykinin, are produced by kallikrein cleavage of kininogen. Kininogen is a hepatic-derived protein which circulates in the blood in a low molecular weight form and a high molecular weight form. Kallikreins can be divided into two groups of serine proteases: tissue kallikreins (EC number 3.4.21.35) and plasma kallikrein (EC number 3.4.21.34). Tissue kallikreins are relatively specific for cleavage of the low molecular weight form of kininogen; plasma kallikrein has greater specificity for the high molecular weight form.
Plasma kallikrein has a molecular weight of about 100 kD, circulates in the blood in a precursor form called prekallikrein, and is principally involved in the activation of the blood clotting and compliment enzyme cascades. Tissue kallikreins, otherwise known as glandular or organ kallikreins, are glycoproteins with a molecular weight ranging from 27–40 kD. They have been isolated from various tissues and body fluids including saliva, intestine, lung, brain, plasma, and the sweat glands of the skin. Their substrates include procollagenase, kininogen, proinsulin, prorenin, BAM 22P atrial natriuretic factor, low density lipoprotein, atriopeptigen, and tissue plasminogen activator.
Angiotensin II is an important factor in blood pressure regulation and in the pathophysiology of renovascular hypertension. Its precursor, angiotensin I, is produced and released into the circulation in response to renin. Angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II, which mediates vasoconstriction via stimulation of the AT1 receptor and the production of bradykinin via stimulation of the AT2 receptor (Siragy and Carey, Hypertension 33: 1214–1217, 1999; Gohlke and Unger, Hypertension 31: 349–355, 1998).